Two generations of spread possible in Indonesia H5N1 cases

May 24, 2006 (CIDRAP News) – For the first time, evidence suggests that the H5N1 avian influenza virus may have passed from one person to another and on to a third, according to a World Health Organization (WHO) official.

Referring to the extended-family case cluster in Indonesia, the WHO's Maria Cheng told the Canadian Press (CP) yesterday, "This is the first time we have seen cases that have gone beyond one generation of human-to-human spread."

The WHO said in an online statement yesterday that analysis of viruses from patients in the cluster had shown no evidence of changes that could lead to efficient human-to-human transmission. But another WHO official expressed serious concern about the cluster.

Peter Cordingley, spokesman for the WHO's Western Pacific region, quoted in a Reuters report today, said, "This is the most significant development so far in terms of public health. We have never had a cluster as large as this. We have not had in the past what we have here, which is no explanation as to how these people became infected [in the first place]. We can't find sick animals in this community, and that worries us."

CDC director not alarmedIn a news briefing this afternoon, the director of the US Centers for Disease Control and Prevention (CDC) generally echoed the WHO's message of yesterday that the cluster appears to involve person-to-person transmission but that there is no sign of transmission beyond the cluster and no evidence of changes in the virus.

"There's a lot more science to be done, but the early indication is we're not seeing anything that would be sending up an alarm," Dr. Julie Gerberding said from Geneva, where she is attending the WHO's annual meeting. She added, "We understand we can't be complacent about this."

The cluster includes seven confirmed cases in an extended family, six of which were fatal. All of these followed a similar illness in a 37-year-old woman who died and was buried without being tested for avian flu. The WHO regards her illness as the index case.

Although other officials have said investigators have not been able to find a possible animal source for the index patient's infection, Gerberding said today, "Clearly the source of infection likely was an infected poultry exposure."

Concurring with the view that at least two generations of transmission occurred, she added, "The person who initially got the infection from poultry may have been the source of transmission to other family members, and there may have been subsequent transmission to other family members." She said the family members had close contact with one another, and there have been no infections in healthcare workers or others outside the family.

Gerberding said that a two-generation, or "person-to-person-to-person," transmission chain is significant in that it raises the "worrisome possibility" of a change in the virus, but added that investigators have not found evidence of a change.

She also said the cluster is not the first example of probable person-to-person transmission of the virus. "This probably the third example where we've seen pretty good evidence of human-to-human transmission," she told reporters.

Gerberding described the people in the cluster as "all related by blood," implying the possibility of genetic susceptibility to the virus. She said it is possible there are some people "who are more susceptible to transmission because of the unique makeup of their respiratory tract. . . . We have no evidence of this, but we have to examine that hypothesis."

The CDC head said the genetic sequencing of viruses from the cluster so far has yielded four main findings:

The isolates are all "virtually identical," implying a single source.

They are susceptible to the antiviral drug Tamiflu (oseltamivir).

"There is no evidence of motif changes in the particular areas of the genes that are responsible for how the virus binds to the respiratory tract of people."

The isolates are very similar to viruses previously collected from poultry in the region.

Gerberding said the cluster occurred in "a Christian community in a pretty remote area on an outlying island." Both traditional and western medical techniques are used in the village. Contrary to some recent reports, she said the local residents have shown "enormous cooperation" with the WHO investigators, at least in the past few days.

Raising the pandemic alert level?The Indonesian cluster has triggered talk about the possibility of the WHO's changing its pandemic alert status from phase 3 to phase 4 on its 6-phase scale, with phase 6 being a full-blown pandemic. A WHO task force would have to meet and make this decision.

"Right now," said the WHO's Cheng in a Reuters story today, "it does not look like the task force will need to meet immediately, but this is subject to change, depending on what comes out of Indonesia."

But the WHO's pandemic alert system lacks specific criteria for elevating the alert level, according to Michael Osterholm, PhD, MPH, director of the Center for Infectious Disease Research and Policy (CIDRAP) at the University of Minnesota, which publishes the CIDRAP Web site.

"I'm personally confused about the difference in what a phase 3 and phase 4 alert level is," he said today. "The WHO has not clearly described the difference.

"That's important. I'm personally aware of a number of companies that have pegged certain levels of their pandemic flu plan based on a change from phase 3 to phase 4. And I'm not sure a change in the alert level would warrant a change in pandemic planning."

The WHO Global Influenza Preparedness Plan (see link below) defines phase 3 as "human infection(s) with a new subtype, but no human-to-human spread, or at most rare instances of spread to a close contact."

Phase 4 is characterized by "small cluster(s) with limited human-to-human transmission, but spread is highly localized, suggesting that the virus is not well adapted to humans."

The WHO plan further states, "The distinction between phase 3, phase 4, and phase 5is based on an assessment of the risk of a pandemic. . . . Factors may include rate of transmission, geographical location and spread, severity of illness, presence of genes from human strains (if derived from an animal strain), and/or other scientific parameters."